Piezo1 Promotes Scleral ECM Remodeling via Mechanical Strain–Induced Fibroblast Differentiation

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Mechanical strain-induced myofibroblast differentiation is a pivotal mechanism underlying scleral extracellular matrix (ECM) remodeling in glaucoma. However, the conversion of mechanical strain into biochemical signals within scleral fibroblasts remains inadequately elucidated. This study sought to investigate the role of Piezo1 in cellular proliferation and differentiation, in the context of mechanical strain-induced myofibroblast differentiation during scleral ECM remodeling. The study design combines in vivo expression observations from a one‑week rat ocular hypertension model with in vitro mechanistic assays using cyclic mechanical stretch (10% at 0.5 Hz for up to 24 h) and pharmacological modulation of Piezo1 (agonist Yoda1, inhibitor GsMTx4, and siRNA knockdown) in primary human scleral fibroblasts (HSF cells). Our findings demonstrate that Piezo1 is expressed in scleral tissue and HSF cells. In the in vivo arm, a significant increase in Piezo1 protein levels was observed in the sclera of ocular hypertensive rats after one week, which coincided with elevated expression of type I collagen (COL1) and α‑smooth muscle actin (α‑SMA). In the in vitro experiments, mechanical stretch (8-24 h) upregulated Piezo1 expression in HSF cells. Moreover, activation of Piezo1 with Yoda1 (24 h) facilitated HSF cell proliferation and enhanced the expression of α‑SMA and COL1. Conversely, knockdown or inhibition of Piezo1 suppressed COL1 expression and hindered myofibroblast differentiation under mechanical strain. Additionally, Piezo1 activation led to an upregulation of Yes‑associated protein (YAP) expression, whereas mechanical strain‑induced YAP expression was diminished upon Piezo1 knockdown or inhibition. In summary, our findings suggest that Piezo1 plays a role in mechanical strain‑induced expression of key ECM components in the sclera in the context of glaucoma and may represent a potential therapeutic target requiring further in vivo validation.

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